Alzheimer's Disease
Conditions
Keywords
Alzheimer's disease cognition SB-742457
Brief summary
The study is designed to investigate the safety and efficacy of SB-742457 when added to stable donepezil treatment in subjects with mild-to-moderate Alzheimer's disease.
Interventions
DRUGSB-742457 15mg
SB-742457 - 15mg added to existing donepezil treatment
DRUGSB-742457 35mg
SB-742457 - 35mg added to existing donepezil
DRUGPlacebo
Placebo added to existing donepezil
DRUGdonepezil 5-10mg
existing donepezil treatment
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Subjects and their caregivers must provide informed consent prior to study entry. * Subjects must have a clinical diagnosis of probable mild-to-moderate Alzheimer's disease with no evidence of disorders that are thought to be the cause of, or contributing to the severity of the subject's dementia and a documented history of at least 6 months of ongoing donepezil therapy with stable dosing for at least the last 2 months. * Subjects must have a regular caregiver who is willing to attend visits, oversee the subject's compliance with the study and report on the subject's status. * Female subjects of child-bearing potential must agree to abstinence or an approved form of birth control. * Subjects must have adequate blood pressure and laboratory values.
Exclusion criteria
* Subjects with a diagnosis of possible, probable or definite vascular dementia may not participate. * Subjects with known hypersensitivity to sunlight or a history of seizures, previous exposure to SB-742457, taking agents for which there is a theoretical risk of interaction with SB-742457, or taking medication for Alzheimer's disease or centrally acting agents which might impact study outcomes may not participate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24 | Baseline(Week 0) and Week 24 | ADAS-cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. There were in all 11 questions. Total scores were calculated as the sum of the individual components. Scores ranged from 0 to 70 with higher scores indicated greater dysfunction. The ADAS-Cog total score was the sum of the calculated scores for questions 1, 2, and 7, and the scores recorded on the case report form (CRF) for questions 3 to 6 and 8 to 11. When a score was missing for one of the questions, the total score was calculated as a weighted average of the scores provided for the remaining ten questions. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean is presented. |
| Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score at Week 24 | Baseline(Week 0) and Week 24 | The CDR-SB is an interviewer administered scale and impairment is scored in each of categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 6 individual category ratings, or box scores, were added together to give the CDR-Sum of Boxes which ranges from 0-18 (severe impairment). If there were any missing items then CDR-SB was set to missing and was not imputed. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in CDR-SB Score at Week 12, 36 and 48 | Baseline (Week 0) and Week 12, 36, 48 | The CDR-SB is an interviewer administered scale and impairment is scored in each of categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 6 individual category ratings, or box scores, were added together to give the CDR-Sum of Boxes which ranges from 0-18 (severe impairment). If there were any missing items then CDR-SB was set to missing and was not imputed. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented. |
| Change From Baseline in RBANS Score at Week 12, 36 and 48 | Baseline (Week 0) and Week 12, 36 and 48 | RBANS is an individually administered cognitive battery comprising 12 subtests across five domains (Attention, Language, Visuospatial/Constructional Abilities, and Immediate and Delayed memory). Total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges between 0 and 311, where a low score indicates greater impairment. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented. |
| Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48 | Baseline (Week 0) and Week 12, 24, 36 and 48 | The ADCS-ADL is an interviewer-administered informant-based scale where the informant (caregiver) responds to 23 activities of daily living questions about the participant. The questions ranged from basic to instrumental activities of daily living and take approximately 20 minutes to complete. The Total score ranges from 0-78 and a higher score signified greater functional ability. The questionnaire was split into two types of questions, an initial question relating to whether a participant had completed a particular activity and then a follow on question which scored how much assistance the participant had required if they had performed that particular activity. The total score was calculated by adding up the responses for each of the individual activities. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented. |
| Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 24 and 48 | Baseline (Week 0) and Week 24 and 48 | The MMSE consisted of 11 items covering orientation, memory (recent and immediate), concentration, language and praxis. Scores ranged from 0 to 30, with lower scores indicating greater cognitive impairment. Scores for each of the 11 individual tests were not recorded on the CRF, therefore if any item was missing then the total score was be set to missing. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During Treatment Phase | Up to follow-up i.e. 2 weeks post end of treatment (Week 24, Week 48 or Early Withdrawal) | An AE was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE was any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. |
| Number of Participants With Parameters of Clinical Concern - Hematology | Up to Week 48 | Only parameters with values have been presented. Data has been reported for number of participants with high and/ or low values for Eosinophils (high-2), Hematocrit (low- 0.8, high-1.2), Lymphocytes (low-0.75, high-1.5), Mean Corpuscle Hemoglobin (MCH) (low-0.8, high-1.2), Monocytes(low-0.75, high-2), Neutrophil bands (high-10), Platelet count (low-100, high-500), Segmented Neutrophils (low-0.75, high-1.3), Total Neutrophils (low-0.75, high-1.5), and white blood cells (WBC) (low-3, high-15). |
| Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24 | Baseline (Week 0) and Week 24 | RBANS is an individually administered cognitive battery comprising 12 subtests across five domains (Attention, Language, Visuospatial/Constructional Abilities, and Immediate and Delayed memory). Total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges between 0 and 311, where a low score indicates greater impairment. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented. |
| Exposure Estimates for SB-742457 : Area Under the Concentration Time Curve Over the Dosing Interval at Steady State (AUCτss) | Post-dose at 3, 8 and 24 hours on Week 0, 1, 3, 6, 12, 18, 24, 30, 36, 42 and 48 | AUCτss of SB-742457 was estimated via nonlinear mixed effect analysis. This pharmacokinetic(PK) model was a steady state one compartment model with first-order absorption, with between participant variability on clearance and volume of distribution. |
| Exposure Estimates for SB-742457 : Minimum Concentrations at Steady State (Cmin-ss) | Post-dose at 3, 8 and 24 hours on Week 0, 1, 3, 6, 12, 18, 24, 30, 36, 42 and 48 | Cmin-ss was estimated via nonlinear mixed effect analysis. This PK model was a steady state one compartment model with first-order absorption, with between participant variability on clearance and volume of distribution. |
| Exposure Estimates for Donepezil (Cavgss) | Post-dose at 12 to 20 hours on Week 0, 1, 3, 6, 12, 18, 24, 30, 36, 42 and 48 | Participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) were allowed to participate in this study. Cavgss for donepezil approximately 12 to 20 hours after dosing were summarized by donepezil dose level 5 mg/7.5 mg/10 mg/15 mg. |
| Change From Baseline in ADAS-Cog Scale in Participants With APOE4 Gene | Baseline (Week 0) to Week 24 and Week 48 | Genetic analyses was conducted to assess the effect of APOE4 carriage. ADAS-cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five-point scale. There were in all 11 questions. Total scores were calculated as the sum of the individual components. Scores ranged from 0 to 70 with higher scores indicating greater dysfunction. The ADAS-Cog total score was the sum of the calculated scores for questions 1, 2, and 7, and the scores were recorded on the CRF for questions 3 to 6 and 8 to 11. When a score was missing for one of the questions, the total score was calculated as a weighted average of the scores provided for the remaining ten questions. Baseline was Week 0 value. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. |
| Change From Baseline in CDR-SB Scale in Participants With APOE4 Gene | Baseline (Week 0) to Week 24 and Week 48 | Genetic analyses was conducted to assess the effect of APOE4 carriage. The CDR-SB is an interviewer administered scale and impairment is scored in following categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment was scored on a scale in which none =0, questionable =0.5, mild =1, moderate =2 and severe =3. The 6 individual category ratings, or box scores, were added together to give the CDR-Sum of Boxes which ranges from 0-18, with higher score indicating severe impairment. If there were any missing items then CDR-SB was set to missing and was not imputed. Baseline was Week 0 value. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. |
| Change From Baseline in RBANS Scale in Participants With APOE4 Gene | Baseline (Week 0) to Week 24 and Week 48 | Genetic analyses was conducted to assess the effect of APOE4 carriage. RBANS is an individually administered cognitive battery comprising 12 subtests across five domains (Attention, Language, Visuospatial/Constructional Abilities, and Immediate and Delayed memory). Total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges between 0 and 311, where a low score indicates greater impairment. Baseline was Week 0 value. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. |
| Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Up to Week 48 | Only parameters with values have been presented. Data has been reported for number of participants with high and/ or low values for Alanine Amino Transferase (ALT) (high-1.5), Alkaline Phosphatase (high-1.5), Aspartate Amino Transferase (ASAT) (high-1.5), BUN/Creatinine ratio (high-1.5), Calcium (low- 0.75, high-1.25), Carbon dioxide content/Bicarbonate (low-15, high- 40), Cholesterol (high-1.25), Creatine Kinase ((low- 0.5, high-1.25), Creatinine (low- 0.5, high-1.25), Direct Bilirubin (high-1.5), Gamma Glutamyl Transferase (GGT) (high-2), Glucose (low- 3.6, high-7.8), HDL Cholesterol (low-0.65), LDL Cholesterol (hig-1.25), Magnesium (low-0.5, high-2), Phosphorus inorganic (low- 0.5, high-1.5), Potassium (low- 3, high-5.5), Sodium (low- 130, high-150), Total Bilirubin (high-1.5), Triglycerides (high -4) and Urea/BUN (high-11). |
| Change From Baseline in ADAS-Cog Total Score at Week 12, 36 and 48 | Baseline (Week 0) and Week 12, 36 and 48 | ADAS-cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. There were in all 11 questions. Total scores were calculated as the sum of the individual components. Scores ranged from 0 to 70 with higher scores indicated greater dysfunction. The ADAS-Cog total score was the sum of the calculated scores for questions 1, 2, and 7, and the scores recorded on the CRF for questions 3 to 6 and 8 to 11. In cases where more than one question was missing, a total score was not be imputed. When a score was missing for one of the questions, the total score was calculated as a weighted average of the scores provided for the remaining ten questions. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been present |
Countries
Argentina, Australia, Canada, Chile, Czechia, Germany, Italy, Spain, United States
Participant flow
Recruitment details
A total of 684 participants were randomized from 100 centers i.e. Australia, Argentina, Chile, Canada, United States of America, Czech Republic, Spain, Italy, Germany between 01 July 2008 and 16 November 2010.
Pre-assignment details
Out of 1132 participants screened, 725 entered into 4-week placebo run-in period out of which 41 participants were placebo run-in failures. Out of 684 participants randomized, 682 were included in safety population (1 participant each from Donepezil+Placebo and Donepezil+SB742457 35 milligram \[mg\] group failed to take a dose of study medication).
Participants by arm
| Arm | Count |
|---|---|
| Donepezil + Placebo Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks. | 223 |
| Donepezil + SB-742457 15 mg Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks. | 218 |
| Donepezil + SB-742457 35 mg Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks. | 236 |
| Total | 677 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 19 | 16 |
| Overall Study | Did not continue after week 24 | 25 | 21 | 16 |
| Overall Study | Lack of Efficacy | 4 | 3 | 5 |
| Overall Study | Lost to Follow-up | 4 | 6 | 7 |
| Overall Study | Missing | 1 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 2 | 4 |
| Overall Study | Protocol Violation | 5 | 5 | 5 |
| Overall Study | Withdrawal by Subject | 24 | 18 | 11 |
Baseline characteristics
| Characteristic | Donepezil + Placebo | Donepezil + SB-742457 15 mg | Donepezil + SB-742457 35 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 73.1 years STANDARD_DEVIATION 7.49 | 74.2 years STANDARD_DEVIATION 6.82 | 73.8 years STANDARD_DEVIATION 6.92 | 73.7 years STANDARD_DEVIATION 7.09 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 223 Participants | 215 Participants | 233 Participants | 671 Participants |
| Sex: Female, Male Female | 129 Participants | 118 Participants | 148 Participants | 395 Participants |
| Sex: Female, Male Male | 94 Participants | 100 Participants | 88 Participants | 282 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 225 | 5 / 221 | 4 / 236 |
| other Total, other adverse events | 41 / 225 | 32 / 221 | 33 / 236 |
| serious Total, serious adverse events | 17 / 225 | 26 / 221 | 27 / 236 |
Outcome results
Primary
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24
ADAS-cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. There were in all 11 questions. Total scores were calculated as the sum of the individual components. Scores ranged from 0 to 70 with higher scores indicated greater dysfunction. The ADAS-Cog total score was the sum of the calculated scores for questions 1, 2, and 7, and the scores recorded on the case report form (CRF) for questions 3 to 6 and 8 to 11. When a score was missing for one of the questions, the total score was calculated as a weighted average of the scores provided for the remaining ten questions. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean is presented.
Time frame: Baseline(Week 0) and Week 24
Population: ITT population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Donepezil + Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24 | 1.2 Score on scale | Standard Error 0.45 |
| Donepezil + SB-742457 15 mg | Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24 | 0.5 Score on scale | Standard Error 0.44 |
| Donepezil + SB-742457 35 mg | Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24 | -0.4 Score on scale | Standard Error 0.41 |
Comparison: SB-742457 15mg versus placebo at Week 24p-value: 0.27995% CI: [-1.9, 0.5]mixed model for repeated measures (MMRM)
Comparison: SB-742457 35mg versus placebo at Week 24p-value: 0.01295% CI: [-2.7, -0.3]MMRM
Primary
Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score at Week 24
The CDR-SB is an interviewer administered scale and impairment is scored in each of categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 6 individual category ratings, or box scores, were added together to give the CDR-Sum of Boxes which ranges from 0-18 (severe impairment). If there were any missing items then CDR-SB was set to missing and was not imputed. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented.
Time frame: Baseline(Week 0) and Week 24
Population: ITT population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Donepezil + Placebo | Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score at Week 24 | 0.9 Score on scale | Standard Error 0.13 |
| Donepezil + SB-742457 15 mg | Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score at Week 24 | 0.8 Score on scale | Standard Error 0.13 |
| Donepezil + SB-742457 35 mg | Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score at Week 24 | 0.7 Score on scale | Standard Error 0.11 |
Comparison: SB-742457 15 mg versus placebo at Week 24p-value: 0.71195% CI: [-0.4, 0.3]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 24p-value: 0.46295% CI: [-0.5, 0.2]MMRM
Secondary
Change From Baseline in ADAS-Cog Scale in Participants With APOE4 Gene
Genetic analyses was conducted to assess the effect of APOE4 carriage. ADAS-cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five-point scale. There were in all 11 questions. Total scores were calculated as the sum of the individual components. Scores ranged from 0 to 70 with higher scores indicating greater dysfunction. The ADAS-Cog total score was the sum of the calculated scores for questions 1, 2, and 7, and the scores were recorded on the CRF for questions 3 to 6 and 8 to 11. When a score was missing for one of the questions, the total score was calculated as a weighted average of the scores provided for the remaining ten questions. Baseline was Week 0 value. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value.
Time frame: Baseline (Week 0) to Week 24 and Week 48
Population: PGx ITT Population consisted of all participants in the ITT population who had evaluable PGx data. Only those participants with APOE gene and available at the specified time point were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Donepezil + Placebo | Change From Baseline in ADAS-Cog Scale in Participants With APOE4 Gene | Week 24 | 1.9 Score on scale | Standard Deviation 5.58 |
| Donepezil + Placebo | Change From Baseline in ADAS-Cog Scale in Participants With APOE4 Gene | Week 48 | 4.7 Score on scale | Standard Deviation 6.52 |
| Donepezil + SB-742457 15 mg | Change From Baseline in ADAS-Cog Scale in Participants With APOE4 Gene | Week 24 | 1.0 Score on scale | Standard Deviation 6.63 |
| Donepezil + SB-742457 15 mg | Change From Baseline in ADAS-Cog Scale in Participants With APOE4 Gene | Week 48 | 4.2 Score on scale | Standard Deviation 7.46 |
| Donepezil + SB-742457 35 mg | Change From Baseline in ADAS-Cog Scale in Participants With APOE4 Gene | Week 24 | -0.1 Score on scale | Standard Deviation 5.4 |
| Donepezil + SB-742457 35 mg | Change From Baseline in ADAS-Cog Scale in Participants With APOE4 Gene | Week 48 | 1.8 Score on scale | Standard Deviation 5.72 |
Secondary
Change From Baseline in ADAS-Cog Total Score at Week 12, 36 and 48
ADAS-cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. There were in all 11 questions. Total scores were calculated as the sum of the individual components. Scores ranged from 0 to 70 with higher scores indicated greater dysfunction. The ADAS-Cog total score was the sum of the calculated scores for questions 1, 2, and 7, and the scores recorded on the CRF for questions 3 to 6 and 8 to 11. In cases where more than one question was missing, a total score was not be imputed. When a score was missing for one of the questions, the total score was calculated as a weighted average of the scores provided for the remaining ten questions. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been present
Time frame: Baseline (Week 0) and Week 12, 36 and 48
Population: ITT population. Only those participants with data available at the specified time points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Donepezil + Placebo | Change From Baseline in ADAS-Cog Total Score at Week 12, 36 and 48 | Week 36 | 2.1 Score on scale | Standard Error 0.45 |
| Donepezil + Placebo | Change From Baseline in ADAS-Cog Total Score at Week 12, 36 and 48 | Week 12 | 0.4 Score on scale | Standard Error 0.33 |
| Donepezil + Placebo | Change From Baseline in ADAS-Cog Total Score at Week 12, 36 and 48 | Week 48 | 3.4 Score on scale | Standard Error 0.52 |
| Donepezil + SB-742457 15 mg | Change From Baseline in ADAS-Cog Total Score at Week 12, 36 and 48 | Week 36 | 2.1 Score on scale | Standard Error 0.48 |
| Donepezil + SB-742457 15 mg | Change From Baseline in ADAS-Cog Total Score at Week 12, 36 and 48 | Week 12 | 0.1 Score on scale | Standard Error 0.37 |
| Donepezil + SB-742457 15 mg | Change From Baseline in ADAS-Cog Total Score at Week 12, 36 and 48 | Week 48 | 3.4 Score on scale | Standard Error 0.6 |
| Donepezil + SB-742457 35 mg | Change From Baseline in ADAS-Cog Total Score at Week 12, 36 and 48 | Week 12 | -0.9 Score on scale | Standard Error 0.34 |
| Donepezil + SB-742457 35 mg | Change From Baseline in ADAS-Cog Total Score at Week 12, 36 and 48 | Week 48 | 1.8 Score on scale | Standard Error 0.5 |
| Donepezil + SB-742457 35 mg | Change From Baseline in ADAS-Cog Total Score at Week 12, 36 and 48 | Week 36 | 0.9 Score on scale | Standard Error 0.45 |
Comparison: SB-742457 15 mg versus placebo at Week 12p-value: 0.63195% CI: [-1.2, 0.7]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 12p-value: 0.00695% CI: [-2.2, -0.4]MMRM
Comparison: SB-742457 15 mg versus placebo at Week 36p-value: 0.94795% CI: [-1.3, 1.2]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 36p-value: 0.05795% CI: [-2.5, 0]MMRM
Comparison: SB-742457 15 mg versus placebo at Week 48p-value: 0.92595% CI: [-1.6, 1.5]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 48p-value: 0.02495% CI: [-3.1, -0.2]MMRM
Secondary
Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48
The ADCS-ADL is an interviewer-administered informant-based scale where the informant (caregiver) responds to 23 activities of daily living questions about the participant. The questions ranged from basic to instrumental activities of daily living and take approximately 20 minutes to complete. The Total score ranges from 0-78 and a higher score signified greater functional ability. The questionnaire was split into two types of questions, an initial question relating to whether a participant had completed a particular activity and then a follow on question which scored how much assistance the participant had required if they had performed that particular activity. The total score was calculated by adding up the responses for each of the individual activities. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented.
Time frame: Baseline (Week 0) and Week 12, 24, 36 and 48
Population: ITT population. Only those participants with data available at the specified time points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Donepezil + Placebo | Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48 | Week 12 | -1.4 Score on scale | Standard Error 0.57 |
| Donepezil + Placebo | Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48 | Week 24 | -3.4 Score on scale | Standard Error 0.66 |
| Donepezil + Placebo | Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48 | Week 36 | -3.7 Score on scale | Standard Error 0.67 |
| Donepezil + Placebo | Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48 | Week 48 | -5.5 Score on scale | Standard Error 0.85 |
| Donepezil + SB-742457 15 mg | Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48 | Week 48 | -5.0 Score on scale | Standard Error 0.87 |
| Donepezil + SB-742457 15 mg | Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48 | Week 12 | -0.8 Score on scale | Standard Error 0.49 |
| Donepezil + SB-742457 15 mg | Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48 | Week 36 | -3.8 Score on scale | Standard Error 0.8 |
| Donepezil + SB-742457 15 mg | Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48 | Week 24 | -1.9 Score on scale | Standard Error 0.61 |
| Donepezil + SB-742457 35 mg | Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48 | Week 48 | -3.5 Score on scale | Standard Error 0.76 |
| Donepezil + SB-742457 35 mg | Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48 | Week 24 | -1.4 Score on scale | Standard Error 0.6 |
| Donepezil + SB-742457 35 mg | Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48 | Week 36 | -1.8 Score on scale | Standard Error 0.65 |
| Donepezil + SB-742457 35 mg | Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48 | Week 12 | 0.3 Score on scale | Standard Error 0.47 |
Comparison: SB-742457 15 mg versus placebo at Week 12p-value: 0.39695% CI: [-0.8, 2.1]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 12p-value: 0.01995% CI: [0.3, 3.2]MMRM
Comparison: SB-742457 15 mg versus placebo at Week 24p-value: 0.1195% CI: [-0.3, 3.2]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 24p-value: 0.02495% CI: [0.3, 3.7]MMRM
Comparison: SB-742457 15 mg versus placebo ate Week 36p-value: 0.94495% CI: [-2.1, 2]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 36p-value: 0.03795% CI: [0.1, 3.8]MMRM
Comparison: SB-742457 15 mg versus placebo at Week 48p-value: 0.70595% CI: [-1.9, 2.9]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 48p-value: 0.08895% CI: [-0.3, 4.2]MMRM
Secondary
Change From Baseline in CDR-SB Scale in Participants With APOE4 Gene
Genetic analyses was conducted to assess the effect of APOE4 carriage. The CDR-SB is an interviewer administered scale and impairment is scored in following categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment was scored on a scale in which none =0, questionable =0.5, mild =1, moderate =2 and severe =3. The 6 individual category ratings, or box scores, were added together to give the CDR-Sum of Boxes which ranges from 0-18, with higher score indicating severe impairment. If there were any missing items then CDR-SB was set to missing and was not imputed. Baseline was Week 0 value. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value.
Time frame: Baseline (Week 0) to Week 24 and Week 48
Population: PGx ITT Population. Only those participants with APOE gene and available at the specified time point were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Donepezil + Placebo | Change From Baseline in CDR-SB Scale in Participants With APOE4 Gene | Week 24 | 1.1 Score on scale | Standard Deviation 2.02 |
| Donepezil + Placebo | Change From Baseline in CDR-SB Scale in Participants With APOE4 Gene | Week 48 | 1.8 Score on scale | Standard Deviation 1.98 |
| Donepezil + SB-742457 15 mg | Change From Baseline in CDR-SB Scale in Participants With APOE4 Gene | Week 24 | 0.6 Score on scale | Standard Deviation 1.59 |
| Donepezil + SB-742457 15 mg | Change From Baseline in CDR-SB Scale in Participants With APOE4 Gene | Week 48 | 1.5 Score on scale | Standard Deviation 2.11 |
| Donepezil + SB-742457 35 mg | Change From Baseline in CDR-SB Scale in Participants With APOE4 Gene | Week 24 | 0.8 Score on scale | Standard Deviation 1.47 |
| Donepezil + SB-742457 35 mg | Change From Baseline in CDR-SB Scale in Participants With APOE4 Gene | Week 48 | 1.4 Score on scale | Standard Deviation 1.92 |
Secondary
Change From Baseline in CDR-SB Score at Week 12, 36 and 48
The CDR-SB is an interviewer administered scale and impairment is scored in each of categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 6 individual category ratings, or box scores, were added together to give the CDR-Sum of Boxes which ranges from 0-18 (severe impairment). If there were any missing items then CDR-SB was set to missing and was not imputed. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented.
Time frame: Baseline (Week 0) and Week 12, 36, 48
Population: ITT population. Only those participants with data available at the specified time points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Donepezil + Placebo | Change From Baseline in CDR-SB Score at Week 12, 36 and 48 | Week 36 | 1.2 Score on scale | Standard Error 0.15 |
| Donepezil + Placebo | Change From Baseline in CDR-SB Score at Week 12, 36 and 48 | Week 12 | 0.5 Score on scale | Standard Error 0.1 |
| Donepezil + Placebo | Change From Baseline in CDR-SB Score at Week 12, 36 and 48 | Week 48 | 1.6 Score on scale | Standard Error 0.16 |
| Donepezil + SB-742457 15 mg | Change From Baseline in CDR-SB Score at Week 12, 36 and 48 | Week 36 | 1.4 Score on scale | Standard Error 0.18 |
| Donepezil + SB-742457 15 mg | Change From Baseline in CDR-SB Score at Week 12, 36 and 48 | Week 12 | 0.4 Score on scale | Standard Error 0.09 |
| Donepezil + SB-742457 15 mg | Change From Baseline in CDR-SB Score at Week 12, 36 and 48 | Week 48 | 1.9 Score on scale | Standard Error 0.2 |
| Donepezil + SB-742457 35 mg | Change From Baseline in CDR-SB Score at Week 12, 36 and 48 | Week 12 | 0.2 Score on scale | Standard Error 0.08 |
| Donepezil + SB-742457 35 mg | Change From Baseline in CDR-SB Score at Week 12, 36 and 48 | Week 48 | 1.5 Score on scale | Standard Error 0.16 |
| Donepezil + SB-742457 35 mg | Change From Baseline in CDR-SB Score at Week 12, 36 and 48 | Week 36 | 1.0 Score on scale | Standard Error 0.13 |
Comparison: SB-742457 15 mg versus placebo at Week 12p-value: 0.38795% CI: [-0.4, 0.1]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 12p-value: 0.01895% CI: [-0.5, -0.1]MMRM
Comparison: SB-742457 15 mg versus placebo at Week 36p-value: 0.43995% CI: [-0.3, 0.6]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 36p-value: 0.33695% CI: [-0.6, 0.2]MMRM
Comparison: SB-742457 15 mg versus placebo at Week 48p-value: 0.1995% CI: [-0.2, 0.8]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 48p-value: 0.78795% CI: [-0.5, 0.4]MMRM
Secondary
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 24 and 48
The MMSE consisted of 11 items covering orientation, memory (recent and immediate), concentration, language and praxis. Scores ranged from 0 to 30, with lower scores indicating greater cognitive impairment. Scores for each of the 11 individual tests were not recorded on the CRF, therefore if any item was missing then the total score was be set to missing. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented.
Time frame: Baseline (Week 0) and Week 24 and 48
Population: ITT population. Only those participants with data available at the specified time points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Donepezil + Placebo | Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 24 and 48 | Week 24 | -0.4 Score on scale | Standard Error 0.21 |
| Donepezil + Placebo | Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 24 and 48 | Week 48 | -1.1 Score on scale | Standard Error 0.28 |
| Donepezil + SB-742457 15 mg | Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 24 and 48 | Week 24 | -0.3 Score on scale | Standard Error 0.23 |
| Donepezil + SB-742457 15 mg | Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 24 and 48 | Week 48 | -1.3 Score on scale | Standard Error 0.33 |
| Donepezil + SB-742457 35 mg | Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 24 and 48 | Week 24 | 0.1 Score on scale | Standard Error 0.21 |
| Donepezil + SB-742457 35 mg | Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 24 and 48 | Week 48 | -0.7 Score on scale | Standard Error 0.27 |
Comparison: SB-742457 15 mg versus placebo at Week 24p-value: 0.96295% CI: [-0.6, 0.6]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 24p-value: 0.13495% CI: [-0.1, 1]MMRM
Comparison: SB-742457 15 mg versus placebo at Week 48p-value: 0.78295% CI: [-1, 0.7]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 48p-value: 0.26895% CI: [-0.3, 1.2]MMRM
Secondary
Change From Baseline in RBANS Scale in Participants With APOE4 Gene
Genetic analyses was conducted to assess the effect of APOE4 carriage. RBANS is an individually administered cognitive battery comprising 12 subtests across five domains (Attention, Language, Visuospatial/Constructional Abilities, and Immediate and Delayed memory). Total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges between 0 and 311, where a low score indicates greater impairment. Baseline was Week 0 value. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value.
Time frame: Baseline (Week 0) to Week 24 and Week 48
Population: PGx ITT Population. Only those participants with APOE gene and available at the specified time point were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Donepezil + Placebo | Change From Baseline in RBANS Scale in Participants With APOE4 Gene | Week 24 | -5.2 Score on scale | Standard Deviation 14.3 |
| Donepezil + Placebo | Change From Baseline in RBANS Scale in Participants With APOE4 Gene | Week 48 | -7.7 Score on scale | Standard Deviation 16.46 |
| Donepezil + SB-742457 15 mg | Change From Baseline in RBANS Scale in Participants With APOE4 Gene | Week 24 | -6.0 Score on scale | Standard Deviation 20.07 |
| Donepezil + SB-742457 15 mg | Change From Baseline in RBANS Scale in Participants With APOE4 Gene | Week 48 | -11.3 Score on scale | Standard Deviation 16.13 |
| Donepezil + SB-742457 35 mg | Change From Baseline in RBANS Scale in Participants With APOE4 Gene | Week 24 | -6.0 Score on scale | Standard Deviation 14.84 |
| Donepezil + SB-742457 35 mg | Change From Baseline in RBANS Scale in Participants With APOE4 Gene | Week 48 | -5.9 Score on scale | Standard Deviation 14.04 |
Secondary
Change From Baseline in RBANS Score at Week 12, 36 and 48
RBANS is an individually administered cognitive battery comprising 12 subtests across five domains (Attention, Language, Visuospatial/Constructional Abilities, and Immediate and Delayed memory). Total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges between 0 and 311, where a low score indicates greater impairment. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented.
Time frame: Baseline (Week 0) and Week 12, 36 and 48
Population: ITT population. Only those participants with data available at the specified time points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Donepezil + Placebo | Change From Baseline in RBANS Score at Week 12, 36 and 48 | Week 36 | -3.9 Score on scale | Standard Error 1.32 |
| Donepezil + Placebo | Change From Baseline in RBANS Score at Week 12, 36 and 48 | Week 12 | -7.2 Score on scale | Standard Error 0.94 |
| Donepezil + Placebo | Change From Baseline in RBANS Score at Week 12, 36 and 48 | Week 48 | -7.3 Score on scale | Standard Error 1.36 |
| Donepezil + SB-742457 15 mg | Change From Baseline in RBANS Score at Week 12, 36 and 48 | Week 36 | -4.8 Score on scale | Standard Error 1.21 |
| Donepezil + SB-742457 15 mg | Change From Baseline in RBANS Score at Week 12, 36 and 48 | Week 12 | -8.5 Score on scale | Standard Error 1.02 |
| Donepezil + SB-742457 15 mg | Change From Baseline in RBANS Score at Week 12, 36 and 48 | Week 48 | -9.4 Score on scale | Standard Error 1.45 |
| Donepezil + SB-742457 35 mg | Change From Baseline in RBANS Score at Week 12, 36 and 48 | Week 12 | -6.5 Score on scale | Standard Error 0.79 |
| Donepezil + SB-742457 35 mg | Change From Baseline in RBANS Score at Week 12, 36 and 48 | Week 48 | -4.7 Score on scale | Standard Error 1.25 |
| Donepezil + SB-742457 35 mg | Change From Baseline in RBANS Score at Week 12, 36 and 48 | Week 36 | -1.8 Score on scale | Standard Error 1.19 |
Comparison: SB-742457 15 mg versus placebo at Week 12p-value: 0.33795% CI: [-4, 1.4]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 12p-value: 0.59695% CI: [-1.7, 3]MMRM
Comparison: SB-742457 15 mg versus placebo at Week 36p-value: 0.63495% CI: [-4.4, 2.7]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 36p-value: 0.23895% CI: [-1.4, 5.6]MMRM
Comparison: SB-742457 15 mg versus placebo at Week 48p-value: 0.29295% CI: [-6, 1.8]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 48p-value: 0.16195% CI: [-1, 6.2]MMRM
Secondary
Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24
RBANS is an individually administered cognitive battery comprising 12 subtests across five domains (Attention, Language, Visuospatial/Constructional Abilities, and Immediate and Delayed memory). Total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges between 0 and 311, where a low score indicates greater impairment. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented.
Time frame: Baseline (Week 0) and Week 24
Population: ITT population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Donepezil + Placebo | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24 | -3.6 Score on scale | Standard Error 1.18 |
| Donepezil + SB-742457 15 mg | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24 | -5.9 Score on scale | Standard Error 1.29 |
| Donepezil + SB-742457 35 mg | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24 | -4.0 Score on scale | Standard Error 1.09 |
Comparison: SB-742457 15 mg versus placebo at Week 24p-value: 0.17495% CI: [-5.8, 1.1]MMRM
Comparison: SB-742457 35 mg versus placebo at Week 24p-value: 0.77695% CI: [-3.6, 2.7]MMRM
Secondary
Exposure Estimates for Donepezil (Cavgss)
Participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) were allowed to participate in this study. Cavgss for donepezil approximately 12 to 20 hours after dosing were summarized by donepezil dose level 5 mg/7.5 mg/10 mg/15 mg.
Time frame: Post-dose at 12 to 20 hours on Week 0, 1, 3, 6, 12, 18, 24, 30, 36, 42 and 48
Population: Donepezil PK population comprised of participants who received a stable dose of donepezil 5 mg/7.5 mg/10 mg/15 mg. Analysis is exclusively for Cavgss of donepezil therefore the two arms SB-742457 15 mg and SB-742457 35 mg have not been presented.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Donepezil + Placebo | Exposure Estimates for Donepezil (Cavgss) | 20.72 ng/mL | Geometric Coefficient of Variation 45.07 |
| Donepezil + SB-742457 15 mg | Exposure Estimates for Donepezil (Cavgss) | 17.68 ng/mL | — |
| Donepezil + SB-742457 35 mg | Exposure Estimates for Donepezil (Cavgss) | 39.79 ng/mL | Geometric Coefficient of Variation 46.62 |
| Donepezil 15 mg | Exposure Estimates for Donepezil (Cavgss) | 36.60 ng/mL | — |
Secondary
Exposure Estimates for SB-742457 : Area Under the Concentration Time Curve Over the Dosing Interval at Steady State (AUCτss)
AUCτss of SB-742457 was estimated via nonlinear mixed effect analysis. This pharmacokinetic(PK) model was a steady state one compartment model with first-order absorption, with between participant variability on clearance and volume of distribution.
Time frame: Post-dose at 3, 8 and 24 hours on Week 0, 1, 3, 6, 12, 18, 24, 30, 36, 42 and 48
Population: PK population included all participants for whom a pharmacokinetic sample was obtained and analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Donepezil + Placebo | Exposure Estimates for SB-742457 : Area Under the Concentration Time Curve Over the Dosing Interval at Steady State (AUCτss) | 1640.76 Nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 35.96 |
| Donepezil + SB-742457 15 mg | Exposure Estimates for SB-742457 : Area Under the Concentration Time Curve Over the Dosing Interval at Steady State (AUCτss) | 4160.29 Nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 31.67 |
Secondary
Exposure Estimates for SB-742457 : Minimum Concentrations at Steady State (Cmin-ss)
Cmin-ss was estimated via nonlinear mixed effect analysis. This PK model was a steady state one compartment model with first-order absorption, with between participant variability on clearance and volume of distribution.
Time frame: Post-dose at 3, 8 and 24 hours on Week 0, 1, 3, 6, 12, 18, 24, 30, 36, 42 and 48
Population: PK population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Donepezil + Placebo | Exposure Estimates for SB-742457 : Minimum Concentrations at Steady State (Cmin-ss) | 53.42 ng/mL | Geometric Coefficient of Variation 38.58 |
| Donepezil + SB-742457 15 mg | Exposure Estimates for SB-742457 : Minimum Concentrations at Steady State (Cmin-ss) | 135.05 ng/mL | Geometric Coefficient of Variation 33.08 |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During Treatment Phase
An AE was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE was any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect.
Time frame: Up to follow-up i.e. 2 weeks post end of treatment (Week 24, Week 48 or Early Withdrawal)
Population: Safety population consisted of all participants randomized to treatment who had received at least one dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Donepezil + Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During Treatment Phase | Any AE | 125 Participants |
| Donepezil + Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During Treatment Phase | Any SAE | 17 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During Treatment Phase | Any AE | 137 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During Treatment Phase | Any SAE | 26 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During Treatment Phase | Any AE | 146 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During Treatment Phase | Any SAE | 27 Participants |
Secondary
Number of Participants With Parameters of Clinical Concern - Clinical Chemistry
Only parameters with values have been presented. Data has been reported for number of participants with high and/ or low values for Alanine Amino Transferase (ALT) (high-1.5), Alkaline Phosphatase (high-1.5), Aspartate Amino Transferase (ASAT) (high-1.5), BUN/Creatinine ratio (high-1.5), Calcium (low- 0.75, high-1.25), Carbon dioxide content/Bicarbonate (low-15, high- 40), Cholesterol (high-1.25), Creatine Kinase ((low- 0.5, high-1.25), Creatinine (low- 0.5, high-1.25), Direct Bilirubin (high-1.5), Gamma Glutamyl Transferase (GGT) (high-2), Glucose (low- 3.6, high-7.8), HDL Cholesterol (low-0.65), LDL Cholesterol (hig-1.25), Magnesium (low-0.5, high-2), Phosphorus inorganic (low- 0.5, high-1.5), Potassium (low- 3, high-5.5), Sodium (low- 130, high-150), Total Bilirubin (high-1.5), Triglycerides (high -4) and Urea/BUN (high-11).
Time frame: Up to Week 48
Population: Safety population. Only those participants with data available at the specified time points were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Total Bilirubin, high | 2 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Magnesium, low | 0 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Creatinine, high | 3 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | BUN/Creatinine ratio, high | 11 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | LDL Cholesterol, high | 35 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Direct Bilirubin, high | 2 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Urea/BUN, high | 17 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | HDL Cholesterol, direct, low | 3 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | GGT, high | 5 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Sodium, high | 0 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Glucose, high | 54 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Glucose, low | 17 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Calcium, low | 0 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Triglycerides, high | 1 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Potassium, high | 2 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Carbon dioxide content/Bicarbonate, low | 3 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | ASAT, high | 2 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | ALT, high | 2 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Cholesterol, high | 11 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Alkaline Phosphatase, high | 5 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Phosphorus, inorganic, high | 0 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Creatine Kinase, high | 5 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Phosphorus, inorganic, high | 0 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | ALT, high | 4 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Alkaline Phosphatase, high | 6 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | ASAT, high | 7 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | BUN/Creatinine ratio, high | 7 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Calcium, low | 0 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Carbon dioxide content/Bicarbonate, low | 2 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Cholesterol, high | 4 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Creatine Kinase, high | 2 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Creatinine, high | 3 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Direct Bilirubin, high | 1 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | GGT, high | 7 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Glucose, low | 24 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Glucose, high | 42 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | HDL Cholesterol, direct, low | 0 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | LDL Cholesterol, high | 29 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Magnesium, low | 1 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Potassium, high | 10 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Sodium, high | 1 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Total Bilirubin, high | 1 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Triglycerides, high | 0 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Urea/BUN, high | 12 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | LDL Cholesterol, high | 40 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Creatine Kinase, high | 6 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Alkaline Phosphatase, high | 4 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Magnesium, low | 0 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Cholesterol, high | 7 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Carbon dioxide content/Bicarbonate, low | 2 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Phosphorus, inorganic, high | 1 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Calcium, low | 1 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Urea/BUN, high | 25 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Potassium, high | 9 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | BUN/Creatinine ratio, high | 5 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Triglycerides, high | 0 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Sodium, high | 1 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Glucose, low | 13 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | GGT, high | 7 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | ASAT, high | 4 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Glucose, high | 54 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Direct Bilirubin, high | 1 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | ALT, high | 4 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | HDL Cholesterol, direct, low | 2 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Creatinine, high | 5 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Total Bilirubin, high | 1 Participants |
Secondary
Number of Participants With Parameters of Clinical Concern - Hematology
Only parameters with values have been presented. Data has been reported for number of participants with high and/ or low values for Eosinophils (high-2), Hematocrit (low- 0.8, high-1.2), Lymphocytes (low-0.75, high-1.5), Mean Corpuscle Hemoglobin (MCH) (low-0.8, high-1.2), Monocytes(low-0.75, high-2), Neutrophil bands (high-10), Platelet count (low-100, high-500), Segmented Neutrophils (low-0.75, high-1.3), Total Neutrophils (low-0.75, high-1.5), and white blood cells (WBC) (low-3, high-15).
Time frame: Up to Week 48
Population: Safety population. Only those participants with data available at the specified time points were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Hematocrit, low | 2 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Segmented Neutrophils, low | 7 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | MCH, low | 0 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Eosinophils, high | 1 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Platelet count, high | 2 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | MCV, low | 0 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Hemoglobin, low | 5 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Platelet count, low | 1 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Monocytes, low | 35 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | WBC, high | 0 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Total Neutrophils, high | 0 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Monocytes, high | 0 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Neutrophil bands, high | 0 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Hemoglobin, high | 3 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | WBC, low | 4 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Total Neutrophils, low | 7 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Lymphocytes, low | 6 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Hematocrit, high | 0 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Segmented Neutrophils, high | 3 Participants |
| Donepezil + Placebo | Number of Participants With Parameters of Clinical Concern - Hematology | Lymphocytes, high | 0 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Total Neutrophils, high | 3 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Eosinophils, high | 0 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Hematocrit, low | 2 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Hematocrit, high | 1 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Hemoglobin, low | 3 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Hemoglobin, high | 1 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Lymphocytes, low | 5 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Lymphocytes, high | 2 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | MCH, low | 1 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | MCV, low | 1 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Neutrophil bands, high | 1 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Monocytes, low | 32 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Monocytes, high | 1 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Platelet count, low | 4 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Platelet count, high | 3 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Segmented Neutrophils, low | 3 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Segmented Neutrophils, high | 4 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Total Neutrophils, low | 3 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | WBC, low | 1 Participants |
| Donepezil + SB-742457 15 mg | Number of Participants With Parameters of Clinical Concern - Hematology | WBC, high | 3 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Hematocrit, low | 1 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Platelet count, high | 5 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Lymphocytes, high | 1 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | WBC, high | 2 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Segmented Neutrophils, low | 7 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Lymphocytes, low | 7 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | WBC, low | 5 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Segmented Neutrophils, high | 5 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Hemoglobin, high | 0 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Eosinophils, high | 4 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Total Neutrophils, low | 7 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Hemoglobin, low | 8 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Monocytes, low | 32 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Hematocrit, high | 0 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Monocytes, high | 0 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Neutrophil bands, high | 1 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | MCV, low | 0 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Total Neutrophils, high | 2 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | Platelet count, low | 3 Participants |
| Donepezil + SB-742457 35 mg | Number of Participants With Parameters of Clinical Concern - Hematology | MCH, low | 0 Participants |